Defining correlates of protection from dengue illness in a long-term cohort study of multigenerational house-holds in Thailand

项目摘要 登革病毒（DENV）导致人类死亡和疾病的重大和不受控制的负担， 我们对DENV的多血清型保护是如何被应用的理解存在重大差距， 产生、维持并随后在免疫测定中鉴定。作为最大的风险， 登革疾病发生继发感染，登革病毒疫苗将需要产生保护作用， 同时使用至少两种血清型，以最大化功效和安全性。我们之前的研究表明， 持久的、多类型的免疫可以通过随时间积累的连续暴露而自然地实现 在登革病毒高流行地区传播。因此，我们的目标是确定儿童的影响， 最早的黄病毒暴露在形成DENV体液免疫表型和亚临床结局中的作用 最近的DENV暴露，产生重要的基准免疫相关的保护。 为了实现这一目标，我们将利用一项正在进行的长期多代家庭队列研究， DENV在泰国Kamphaeng Phet的传播。该队列于2015年建立，利用NIH P01 和美国国防部的资金，并已登记超过3000个人在500个家庭。432例原发性登革病毒感染 到目前为止，在814名登革病毒初治儿童中已经确定了，到2010年底将确定更多的登革病毒初治儿童。 研究期间为2028年，标志着连续监测13年。通过以下方式识别偶发感染 每季度进行一次抽样，以检测血清转化，并积极监测急性登革热疾病。我们 将通过胎盘转移和母乳喂养将母体转移的免疫水平与 在750对母婴（包括500名以前登记的和 250例新入组的二联体）（目标1）。接下来，我们将继续对登革病毒初治儿童进行长期随访， 鉴定与保护免于疾病相关同种型和抗原特异性DENV抗体表型， 原发后DENV感染（目的2）。最后，我们将把非DENV黄病毒暴露（日本脑炎） 寨卡病毒（Zika virus，Zika virus，JEV）疫苗接种、寨卡病毒（Zika virus，Zika virus）感染、JEV感染 暴露后时间、感染前抗体表型和JEV疫苗类型的影响（目的3）。 这些活动符合NIAID的使命，即更好地了解、治疗和最终预防感染。 一些疾病。该应用是创新的，使用定制的多重面板来分析DENV抗体， 唾液，允许频繁的纵向采样，并使用先进的建模技术来重建 免疫动力学和鉴定亚临床感染。成功完成研究目标将代表一个IM- 重要的进展，以确定持久的免疫相关性，多血清型保护对登革病毒， gue疾病，为诊断，分诊和DENV疫苗和免疫疗法提供关键基准。

PROJECT SUMMARY Dengue viruses (DENV) cause a significant and unchecked burden of human death and disease, with vaccine development hindered by critical gaps in our understanding of how multi-serotypic protection against DENV is generated, sustained, and subsequently identified in immunological assays. As the greatest risk for severe dengue illness occurs with secondary infection, DENV vaccines will need to generate protection against at least two serotypes simultaneously to maximize efficacy and safety. Our prior studies have demonstrated that durable, multi-typic immunity can be achieved naturally, through sequential exposures accumulated over time in hyperendemic areas for DENV transmission. Accordingly, our objective is to define the impacts of a child’s earliest flavivirus exposures in shaping DENV humoral immune phenotypes and clinical outcomes of subse- quent DENV exposures, generating important benchmarks for immune correlates of protection. To address this objective, we will leverage an ongoing long-term multigenerational family cohort study for DENV transmission in Kamphaeng Phet, Thailand. The cohort was established in 2015, leveraging NIH P01 and US DOD funds, and has enrolled over 3000 individuals within 500 families. 432 primary DENV infections have been identified among 814 DENV-naïve children to date, with more to be identified by the end of the study period in 2028 and marking 13 years of continuous surveillance. Incident infections are identified through quarterly sampling to detect seroconversions and through active surveillance for acute dengue illnesses. We will relate levels of maternally-transferred immunity, through placental transfer and breastfeeding, to risks of dengue illness with primary DENV infection in 750 mother-infant dyads (including 500 previously-enrolled and 250 newly-enrolled dyads) (Aim 1). Next, we will continue our long-term follow-up of DENV-naïve children and identify isotype- and antigen-specific DENV antibody phenotypes associated with protection from illness with post-primary DENV infection (Aim 2). Finally, we will relate non-DENV flavivirus exposures (Japanese enceph- alitis virus [JEV] vaccination, Zika virus infection, JEV infection) to risks of subsequent dengue illness, defining effects of time since exposure, pre-infection antibody phenotypes, and JEV vaccine type (Aim 3). These activities are consistent with NIAID’s mission to better understand, treat, and ultimately prevent infec- tious diseases. The application is innovative in using a custom multiplex panel for profiling DENV antibodies in saliva, permitting frequent longitudinal sampling, and in using advanced modeling techniques to reconstruct immune kinetics and identify subclinical infections. Successful completion of study aims will represent an im- portant advancement towards identifying immune correlates of durable, multi-serotypic protection against den- gue illness, providing critical benchmarks for diagnostics, triage, and DENV vaccines and immuno-therapies.